N,N&#39;-Diphenylurea Derivatives Which are Suitable as Kinase Inhibitors

ABSTRACT

Compounds of the formula (I), in which R 1a —R 1c , R 2a , R 2b , R 3  and R 5  have the meanings indicated in claim  1 , are inhibitors of tyrosine kinases, in particular TIE-2, and Raf kinases and can be employed, inter alia, for the treatment of tumours.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to compounds and to the use of compoundsin which the inhibition, regulation and/or modulation of kinase signaltransduction, in particular tyrosine kinase and/or serine/threoninekinase signal transduction, plays a role, furthermore to pharmaceuticalcompositions which comprise these compounds, and to the use of thecompounds for the treatment of kinase-induced diseases.

Specifically, the present invention relates to compounds of the formulaI which inhibit, regulate and/or modulate tyrosine kinase signaltransduction, to compositions which comprise these compounds, and tomethods for the use thereof for the treatment of tyrosine kinase-induceddiseases and conditions, such as angiogenesis, cancer, tumour formation,growth and propagation, arteriosclerosis, ocular diseases, such asage-induced macular degeneration, choroidal neovascularisation anddiabetic retinopathy, inflammatory diseases, arthritis, thrombosis,fibrosis, glomerulonephritis, neurodegeneration, psoriasis, restenosis,wound healing, transplant rejection, metabolic and diseases of theimmune system, also autoimmune diseases, cirrhosis, diabetes anddiseases of the blood vessels, including instability and permeability,and the like, in mammals.

Tyrosine kinases are a class of enzymes with at least 400 members whichcatalyse the transfer of the terminal phosphate of adenosinetriphosphate (gamma-phosphate) to tyrosine residues in proteinsubstrates. It is thought that tyrosine kinases, through substratephosphorylation, play a crucial role in signal transduction in variouscellular functions. Although the precise mechanisms of signaltransduction are still unclear, tyrosine kinases have been shown to beimportant factors in cell proliferation, carcinogenesis and celldifferentiation.

Tyrosine kinases can be divided into receptor-type tyrosine kinases andnon-receptor-type tyrosine kinases. Receptor-type tyrosine kinases havean extracellular portion, a transmembrane portion and an intracellularportion, while non-receptor-type tyrosine kinases are exclusivelyintracellular (see reviews by Schlessinger and Ullrich, Neuron 9,383-391 (1992) and 1-20 (1992)).

Receptor-type tyrosine kinases consist of a multiplicity oftransmembrane receptors with different biological activity. Thus, about20 different sub-families of receptor-type tyrosine kinases have beenidentified. One tyrosine kinase subfamily, known as the HER subfamily,consists of EGFR, HER2, HER3 and HER4. Ligands from this subfamily ofreceptors include epithelial growth factor, TGF-α, amphiregulin, HB-EGF,betacellulin and heregulin. Another subfamily of these receptor-typetyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IRand IR-R. The PDGF sub-family includes the PDGF-α and -β receptors,CSFIR, c-kit and FLK-II. In addition, there is the FLK family, whichconsists of the kinase insert domain receptor (KDR), foetal liverkinase-1 (FLK-1), foetal liver kinase-4 (FLK-4) and fms tyrosinekinase-1 (fit-1). The PDGF and FLK families are usually discussedtogether due to the similarities between the two groups. For a detaileddiscussion of receptor-type tyrosine kinases, see the paper by Plowmanet al., DN & P 7(6):334-339, 1994, which is hereby incorporated by wayof reference.

The RTKs (receptor-type tyrosine kinases) also include TIE2 and itsligands angiopoietin 1 and 2. More and more homologues of these ligandshave now been found, the action of which has not yet been demonstratedclearly in detail. TIE1 is known as a homologue of TIE2. The TIE RTKsare expressed selectively on endothelial cells and are involved inprocesses of angiogenesis and maturing of the blood vessels. They mayconsequently be a valuable aim, in particular, in diseases of thevascular system and in pathologies in which vessels are utilised or evenreformed. In addition to prevention of neovascularisation and maturing,stimulation of neovascularisation may also be a valuable aim for activeingredients. Reference is made to review papers on angiogenesis, tumourdevelopment and kinase signal transduction by

G. Breier Placenta (2000) 21, Suppl A, Trophoblasr Res 14, S11-S15

F. Bussolino et al. TIBS 22, 251-256 (1997)

G. Bergers & L. E. Benjamin Nature Rev Cancer 3, 401-410 (2003) P.Blume-Jensen &. Hunter Nature 411, 355-365 (2001)

M. Ramsauer & P. D'Amore J. Clin. INvest. 110, 1615-1617 (2002)S. Tsigkos et al. Expert Opin. Investig. Drugs 12, 933-941 (2003)

Examples of kinase inhibitors which have already been tested in cancertherapy are given in L. K. Shawyer et al. Cancer Cell 1, 117-123 (2002)and D. Fabbro & C. Garcia-Echeverria Current Opin. Drug Discovery &Development 5, 701-712 (2002).

Non-receptor-type tyrosine kinases likewise consist of a multiplicity ofsubfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak,Jak, Ack, and LIMK. Each of these subfamilies is further sub-dividedinto different receptors. For example, the Src subfamily is one of thelargest subfamilies. It includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgrand Yrk. The Src sub-family of enzymes has been linked to oncogenesis.For a more detailed discussion of non-receptor-type tyrosine kinases,see the paper by Bolen Oncogene, 8:2025-2031 (1993), which is herebyincorporated by way of reference.

Both receptor-type tyrosine kinases and non-receptor-type tyrosinekinases are involved in cellular signal transduction pathways leading tovarious pathogenic conditions, including cancer, psoriasis andhyperimmune responses.

It has been proposed that various receptor-type tyrosine kinases, andthe growth factors binding to them, play a role in angiogenesis,although some may promote angiogenesis indirectly (Mustonen and Alitalo,J. Cell Biol. 129:895-898, 1995). One of these receptor-type tyrosinekinases is foetal liver kinase 1, also referred to as FLK-1. The humananalogue of FLK-1 is the kinase insert domain-containing receptor KDR,which is also known as vascular endothelial cell growth factor receptor2 or VEGFR-2, since it binds VEGF with high affinity. Finally, themurine version of this receptor has also been called NYK (Oelrichs etal., Oncogene 8(1):11-15,1993). VEGF and KDR are a ligand-receptor pairwhich plays a vital role in the proliferation of vascular endothelialcells and the formation and sprouting of blood vessels, referred to asvasculogenesis and angiogenesis respectively.

Angiogenesis is characterised by excessive activity of vascularendothelial growth factor (VEGF). VEGF actually consists of a family ofligands (Klags-burn and D'Amore, Cytokine & Growth Factor Reviews7:259-270, 1996). VEGF binds the high affinity membrane-spanningtyrosine kinase receptor KDR and the related fms tyrosine kinase-1, alsoknown as Flt-1 or vascular endothelial cell growth factor receptor 1(VEGFR-1). Cell culture and gene knockout experiments indicate that eachreceptor contributes to different aspects of angiogenesis. KDR mediatesthe mitogenic function of VEGF, whereas Flt-1 appears to modulatenon-mitogenic functions, such as those associated with cellularadhesion. Inhibiting KDR thus modulates the level of mitogenic VEGFactivity. In fact, tumour growth has been shown to be susceptible to theantiangiogenic effect of VEGF receptor antagonists (Kim et al., Nature362, pp. 841-844,1993).

Three PTK (protein tyrosine kinase) receptors for VEGFR have beenidentified: VEGFR-1 (Flt-1); VEGRF-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4).VEGFR-2 is of particular interest.

Solid tumours can therefore be treated with tyrosine kinase inhibitorssince these tumours depend on angiogenesis for the formation of theblood vessels that are necessary to support their growth. These solidtumours include monocytic leukaemia, brain, urogenital, lymphaticsystem, stomach, laryngeal and lung carcinoma, including lungadenocarcinoma and small-cell lung carcinoma. Further examples includecarcinomas in which overexpression or activation of Raf-activatingoncogenes (for example K-ras, erb-B) is observed. These carcinomasinclude pancreatic and breast carcinoma. Inhibitors of these tyrosinekinases are therefore suitable for the prevention and treatment ofproliferative diseases caused by these enzymes.

The angiogenic activity of VEGF is not limited to tumours. VEGF accountsfor the angiogenic activity produced in or near the retina in diabeticretinopathy. This vascular growth in the retina leads to visualdegeneration culminating in blindness. Ocular VEGF mRNA and proteinlevels are elevated by conditions such as retinal vein occlusion inprimates and decreased pO₂ level in mice that lead toneovascularisation. Intraocular injections of anti-VEGF monoclonalantibodies or VEGF receptor immunofusions inhibit ocularneovascularisation in both primate and rodent models. Irrespective ofthe cause of induction of VEGF in human diabetic retinopathy, inhibitionof ocular VEGF is suitable for treating this disease.

Expression of VEGF is also significantly increased in hypoxic regions ofanimal and human tumours adjacent to areas of necrosis. In addition,VEGF is upregulated by the expression of the ras, raf, src and p53mutant oncogenes (all of which are important in combating cancer).Anti-VEGF monoclonal antibodies inhibit the growth of human tumours innude mice. Although the same tumour cells continue to express VEGF inculture, the antibodies do not diminish their mitotic rate. Thus,tumour-derived VEGF does not function as an autocrine mitogenic factor.VEGF therefore contributes to tumour growth in vivo by promotingangiogenesis through its paracrine vascular endothelial cell chemotacticand mitogenic activities. These monoclonal antibodies also inhibit thegrowth of typically less well vascularized human colon carcinomas inathymic mice and decrease the number of tumours arising from inoculatedcells.

The expression of a VEGF-binding construct of Flk-1, Flt-1, the mouseKDR receptor homologue truncated to eliminate the cytoplasmic tyrosinekinase domains but retaining a membrane anchor, in viruses virtuallystops the growth of a transplantable glioblastoma in mice, presumably bythe dominant negative mechanism of heterodimer formation withmembrane-spanning endothelial cell VEGF receptors. Embryonic stem cells,which normally grow as solid tumours in nude mice, do not producedetectable tumours if both VEGF alleles are knocked out. Taken together,these data indicate the role of VEGF in the growth of solid tumours.Inhibition of KDR or Flt-1 is involved in pathological angiogenesis, andthese receptors are suitable for the treatment of diseases in whichangiogenesis is part of the overall pathology, for example inflammation,diabetic retinal vascularisation, as well as various forms of cancer,since tumour growth is known to be dependent on angiogenesis (Weidner etal., N. Engl. J. Med., 324, pp. 1-8, 1991).

Angiopoietin 1 (Ang1), a ligand for the endothelium-specificreceptor-type tyrosine kinase TIE-2, is a novel angiogenic factor (Daviset al, Cell, 1996, 87:1161-1169; Partanen et al, Mol. Cell. Biol.,12:1698-1707 (1992); U.S. Pat. Nos. 5,521,073; 5,879,672; 5,877,020; and6,030,831). The acronym TIE stands for “tyrosine kinase with Ig and EGFhomology domains”. TIE is used for the identification of a class ofreceptor-type tyrosine kinases which are expressed exclusively invascular endothelial cells and early haemopoietic cells. TIE receptorkinases are typically characterised by the presence of an EGF-likedomain and an immunoglobulin (IG)-like domain which consists ofextracellular fold units stabilised by disulfide bridge bonds betweenthe chains (Partanen et al Curr. Topics Microbiol. Immunol., 1999,237:159-172). In contrast to VEGF, which exerts its function during theearly stages of vascular development, Ang1 and its receptor TIE-2 actduring the later stages of vascular development, i.e. during vasculartransformation (transformation relates to the formation of a vascularlumen) and maturing (Yancopoulos et al, Cell, 1998, 93:661-664; Peters,K. G., Circ. Res., 1998, 83(3):342-3; Suri et al, Cell 87, 1171-1180(1996)).

Accordingly, it would be expected that inhibition of TIE-2 shouldinterrupt the transformation and maturing of a new vascular systeminitiated by angiogenesis and should thus interrupt the angiogenesisprocess. Furthermore, inhibition at the kinase domain binding site ofVEGFR-2 would block phosphorylation of tyrosine residues and serve tointerrupt initiation of angiogenesis. It must therefore be assumed thatinhibition of TIE-2 and/or VEGFR-2 should prevent tumour angiogenesisand serve to slow or completely eliminate tumour growth. Accordingly,treatment of cancer and other diseases associated with inappropriateangiogenesis could be provided.

The present invention is directed to methods for the regulation,modulation or inhibition of TIE-2 for the prevention and/or treatment ofdiseases associated with irregular or disturbed TIE-2 activity. Inparticular, the compounds of the formula I can also be employed in thetreatment of certain forms of cancer. Furthermore, the compounds of theformula I can be used to provide additive or synergistic effects incertain existing cancer chemotherapies and/or can be used to restore theefficacy of certain existing cancer chemotherapies and radiotherapies.

The compounds of the formula I can furthermore be used for the isolationand investigation of the activity or expression of TIE-2. In addition,they are particularly suitable for use in diagnostic methods fordiseases associated with irregular or disturbed TIE-2 activity.

The present invention is furthermore directed to methods for theregulation, modulation or inhibition of VEGFR-2 for the preventionand/or treatment of diseases associated with irregular or disturbedVEGFR-2 activity.

The present invention furthermore relates to the compounds of theformula I as inhibitors of Raf kinases.

Protein phosphorylation is a fundamental process for the regulation ofcellular functions. The coordinated action of both protein kinases andphosphatases controls the degrees of phosphorylation and, hence, theactivity of specific target proteins. One of the predominant roles ofprotein phosphorylation is in signal transduction, where extracellularsignals are amplified and propagated by a cascade of proteinphosphorylation and dephosphorylation events, for example in the p21ras/raf pathway.

The p21^(ras) gene was discovered as an oncogene of the Harvey (H-Ras)and Kirsten (K-Ras) rat sarcoma viruses. In humans, characteristicmutations in the cellular Ras gene (c-Ras) have been associated withmany different types of cancer. These mutant alleles, which render Rasconstitutively active, have been shown to transform cells, such as, forexample, the murine cell line NIH 3T3, in culture.

The p21^(ras) oncogene is a major contributor to the development andprogression of human solid carcinomas and is mutated in 30% of all humancarcinomas (Bolton et al. (1994) Ann. Rep. Med. Chem., 29, 165-74; Bos.(1989) Cancer Res., 49, 4682-9). In its normal, unmutated form, the Rasprotein is a key element of the signal transduction cascade directed bygrowth factor receptors in almost all tissues (Avruch et al. (1994)Trends Biochem. Sci., 19, 279-83).

Biochemically, Ras is a guanine nucleotide binding protein, and cyclingbetween a GTP-bound activated and a GDP-bound resting form is strictlycontrolled by Ras endogenous GTPase activity and other regulatoryproteins. The Ras gene product binds to guanine triphosphate (GTP) andguanine diphosphate (GDP) and hydrolyses GTP to GDP. Ras is active inthe GTP-bound state. In the Ras mutants in cancer cells, the endogenousGTPase activity is reduced and the protein consequently transmitsconstitutive growth signals to downstream effectors, such as, forexample, the enzyme Raf kinase. This leads to the cancerous growth ofthe cells which carry these mutants (Magnuson et al. (1994) Semin.Cancer Biol., 5, 247-53). The Ras proto-oncogene requires a functionallyintact C-Raf-1 proto-oncogene in order to transduce growth anddifferentiation signals initiated by receptor- and non-receptor-typetyrosine kinases in higher eukaryotes.

Activated Ras is necessary for the activation of the C-Raf-1proto-oncogene, but the biochemical steps through which Ras activatesthe Raf-1 protein (Ser/Thr) kinase are now well characterised. It hasbeen shown that inhibiting the effect of active Ras by inhibiting theRaf kinase signalling pathway by administration of deactivatingantibodies to Raf kinase or by co-expression of dominant negative Rafkinase or dominant negative MEK (MAPKK), the substrate of Raf kinase,leads to reversion of transformed cells to the normal growth phenotype,see: Daum et al. (1994) Trends Biochem. Sci., 19, 474-80; Fridman et al.(1994) J. Biol. Chem., 269, 30105-8. Kolch et al. (1991) Nature, 349,426-28) and for a review Weinstein-Oppenheimer et al. Pharm. & Therap.(2000), 88, 229-279.

Similarly, inhibition of Raf kinase (by antisense oligodeoxynucleotides)has been correlated in vitro and in vivo with inhibition of the growthof a variety of human tumour types (Monia et al., Nat. Med. 1996, 2,668-75).

Raf serine- and threonine-specific protein kinases are cytosolic enzymesthat stimulate cell growth in a variety of cellular systems (Rapp, U.R., et al. (1988) in The Oncogene Handbook; T. Curran, E. P. Reddy andA. Skalka (eds.) Elsevier Science Publishers; The Netherlands, pp.213-253; Rapp, U. R., et al. (1988) Cold Spring Harbor Sym. Quant. Biol.53:173-184; Rapp, U. R., et al. (1990) Inv Curr. Top. Microbiol.Immunol. Potter and Melchers (eds.), Berlin, Springer-Verlag166:129-139).

Three isozymes have been characterised:

C-Raf (Raf-1) (Bonner, T. I., et al. (1986) Nucleic Acids Res.14:1009-1015). A-Raf (Beck, T. W., et al. (1987) Nucleic Acids Res.15:595-609), and B-Raf (Qkawa, S., et al. (1998) Mol. Cell. Biol.8:2651-2654; Sithanandam, G. et al. (1990) Oncogene: 1775). Theseenzymes differ in their expression in various tissues. Raf-1 isexpressed in all organs and in all cell lines that have been examined,and A- and B-Raf are expressed in urogenital and brain tissuesrespectively (Storm, S. M. (1990) Oncogene 5:345-351).

Raf genes are proto-oncogenes: they can initiate malignanttransformation of cells when expressed in specifically altered forms.Genetic changes that lead to oncogenic activation generate aconstitutively active protein kinase by removal of or interference withan N-terminal negative regulatory domain of the protein (Heidecker, G.,et al. (1990) Mol. Cell. Biol. 10:2503-2512; Rapp, U. R., et al. (1987)in Oncogenes and Cancer; S. A. Aaronson, J. Bishop, T. Sugimura, M.Terada, K. Toyoshima and P. K. Vogt (eds.) Japan Scientific Press,Tokyo). Microinjection into NIH 3T3 cells of onco-genically activated,but not wild-type, versions of the Raf protein prepared with Escherichiacoli expression vectors results in morphological transformation andstimulates DNA synthesis (Rapp, U. R., et al. (1987) in Oncogenes andCancer; S. A. Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima,and P. K. Vogt (eds.) Japan Scientific Press, Tokyo; Smith, M. R., etal. (1990) Mol. Cell. Biol. 10:3828-3833).

Consequently, activated Raf-1 is an intracellular activator of cellgrowth. Raf-1 protein serine kinase is a candidate for the downstreameffector of mitogen signal transduction, since Raf oncogenes overcomegrowth arrest resulting from a block of cellular Ras activity due eitherto a cellular mutation (Ras revertant cells) or microinjection ofanti-Ras antibodies (Rapp, U. R., et al. (1988) in The OncogeneHandbook, T. Curran, E. P. Reddy and A. Skalka (eds.), Elsevier SciencePublishers; The Netherlands, pp. 213-253; Smith, M. R., et al. (1986)Nature (London) 320:540-543).

C-Raf function is required for transformation by a variety ofmembrane-bound oncogenes and for growth stimulation by mitogenscontained in serums (Smith, M. R., et al. (1986) Nature (London)320:540-543). Raf-1 protein serine kinase activity is regulated bymitogens via phosphorylation (Morrison, D. K., et al. (1989) Cell58:648-657), which also effects sub-cellular distribution (Olah, Z., etal. (1991) Exp. Brain Res. 84:403; Rapp, U. R., et al. (1988) ColdSpring Harbor Sym. Quant. Biol. 53:173-184. Raf-1 activating growthfactors include platelet-derived growth factor (PDGF) (Morrison, D. K.,et al. (1988) Proc. Natl. Acad. Sci. USA 85:8855-8859),colony-stimulating factor (Baccarini, M., et al. (1990) EMBO J.9:3649-3657), insulin (Blackshear, P. J., et al. (1990) J. Biol. Chem.265:12115-12118), epidermal growth factor (EGF) (Morrison, R. K., et al.(1988) Proc. Natl. Acad. Sci. USA 85:8855-8859), interleukin-2 (Turner,B. C., et al. (1991) Proc. Natl. Acad. Sci. USA 88:1227) andinterleukin-3 and granulocyte macrophage colony-stimulating factor(Carroll, M. P., et al. (1990) J. Biol. Chem. 265:19812-19817).

After mitogen treatment of cells, the transiently activated Raf-1protein serine kinase translocates to the perinuclear area and thenucleus (Olah, Z., et al. (1991) Exp. Brain Res. 84:403; Rapp, U. R., etal. (1988) Cold Spring Harbor Sym. Quant. Biol. 53:173-184). Cellscontaining activated Raf are altered in their pattern of gene expression(Heidecker, G., et al. (1989) in Genes and signal transduction inmultistage carcinogenesis, N. Colburn (ed.), Marcel Dekker, Inc., NewYork, pp. 339-374) and Raf oncogenes activate transcription fromAp-I/PEA3-dependent promoters in transient transfection assays (Jamal,S., et al. (1990) Science 344:463-466; Kaibuchi, K., et al. (1989) J.Biol. Chem. 264:20855-20858; Wasylyk, C., et al. (1989) Mol. Cell. Biol.9:2247-2250).

There are at least two independent pathways for Raf-1 activation byextracellular mitogens: one involving protein kinase C (KC) and a secondinitiated by protein tyrosine kinases (Blackshear, P. J., et al. (1990)J. Biol. Chem. 265:12131-12134; Kovacina, K. S., et al. (1990) J. Biol.Chem. 265:12115-12118; Morrison, D. K., et al. (1988) Proc. Natl. Acad.Sci. USA 85:8855-8859; Siegel, J. N., et al. (1990) J. Biol. Chem.265:18472-18480; Turner, B. C., et al. (1991) Proc. Natl. Acad. Sci. USA88:1227). In each case, activation involves Raf-1 proteinphosphorylation. Raf-1 phosphorylation may be a consequence of a kinasecascade amplified by autophosphorylation or may be caused entirely byautophosphorylation initiated by binding of a putative activating ligandto the Raf-1 regulatory domain, analogous to PKC activation bydiacylglycerol (Nishizuka, Y. (1986) Science 233:305-312).

One of the principal mechanisms by which cellular regulation is effectedis through the transduction of extracellular signals across the membranethat in turn modulate biochemical pathways within the cell. Proteinphosphorylation represents one course by which intracellular signals arepropagated from molecule to molecule resulting finally in a cellularresponse. These signal transduction cascades are highly regulated andoften overlap, as is evident from the existence of many protein kinasesas well as phosphatases. Phosphorylation of proteins occurspredominantly at serine, threonine or tyrosine residues, and proteinkinases have therefore been classified by their specificity ofphosphorylation site, i.e. serine/threonine kinases and tyrosinekinases. Since phosphorylation is such a ubiquitous process within cellsand since cellular phenotypes are largely influenced by the activity ofthese pathways, it is currently believed that a number of disease statesand/or diseases are attributable to either aberrant activation orfunctional mutations in the molecular components of kinase cascades.Consequently, considerable attention has been devoted to thecharacterisation of these proteins and compounds that are able tomodulate their activity (for a review see: Weinstein-Oppenheimer et al.Pharma. &. Therap., 2000, 88, 229-279).

The synthesis of small compounds which specifically inhibit, regulateand/or modulate tyrosine kinase and/or Raf kinase signal transduction istherefore desirable and an aim of the present invention.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

In particular, they exhibit tyrosine kinase inhibiting properties.

It has furthermore been found that the compounds according to theinvention are inhibitors of the enzyme Raf kinase. Since the enzyme is adown-stream effector of p21^(ras), the inhibitors prove to be suitablein pharmaceutical compositions for use in human or veterinary medicinewhere inhibition of the Raf kinase pathway is indicated, for example inthe treatment of tumours and/or cancerous cell growth mediated by Rafkinase. In particular, the compounds are suitable for the treatment ofhuman and animal solid cancers, for example murine cancer, since theprogression of these cancers is dependent upon the Ras protein signaltransduction cascade and therefore susceptible to treatment byinterruption of the cascade, i.e. by inhibiting Raf kinase. Accordingly,the compound according to the invention or a pharmaceutically acceptablesalt thereof is administered for the treatment of diseases mediated bythe Raf kinase pathway, especially cancer, including solid cancers, suchas, for example, carcinomas (for example of the lungs, pancreas,thyroid, bladder or colon), myeloid diseases (for example myeloidleukaemia) or adenomas (for example villous colon adenoma), pathologicalangiogenesis and metastatic cell migration. The compounds arefurthermore suitable for the treatment of complement activationdependent chronic inflammation (Niculescu et al. (2002) Immunol. Res.,24:191-199) and HIV-1 (human immunodeficiency virus type 1) inducedimmunodeficiency (Popik et al. (1998) J Virol, 72: 6406-6413).

Surprisingly, it has been found that the compounds according to theinvention are able to interact with signalling pathways, especially thesignalling pathways described herein and preferably the Raf kinasesignalling pathway. The compounds according to the invention preferablyexhibit an advantageous biological activity which is easily demonstratedin enzyme-based assays, for example assays as described herein. In suchenzyme-based assays, the compounds according to the invention preferablyexhibit and cause an inhibiting effect, which is usually documented byIC₅₀ values in a suitable range, preferably in the micromolar range andmore preferably in the nanomolar range.

As discussed herein, these signalling pathways are relevant for variousdiseases. Accordingly, the compounds according to the invention aresuitable for the prophylaxis and/or treatment of diseases that aredependent on the said signalling pathways by interacting with one ormore of the said signalling pathways.

The present invention therefore relates to compounds according to theinvention as promoters or inhibitors, preferably as inhibitors, of thesignalling pathways described herein. The invention therefore preferablyrelates to compounds according to the invention as promoters orinhibitors, preferably as inhibitors, of the Raf kinase pathway. Theinvention therefore preferably relates to compounds according to theinvention as promoters or inhibitors, preferably as inhibitors, of Rafkinase. The invention still more preferably relates to compoundsaccording to the invention as promoters or inhibitors, preferably asinhibitors, of one or more Raf kinases selected from the groupconsisting of A-Raf, B-Raf and C-Raf-1. The invention particularlypreferably relates to compounds according to the invention as promotersor inhibitors, preferably as inhibitors, of C-Raf-1.

The present invention furthermore relates to the use of one or morecompounds according to the invention in the treatment and/or prophylaxisof diseases, preferably the diseases described herein, that are caused,mediated and/or propagated by Raf kinases and in particular diseasesthat are caused, mediated and/or propagated by Raf kinases selected fromthe group consisting of A-Raf, B-Raf and C-Raf-1. The diseases discussedherein are usually divided into two groups, hyperproliferative andnon-hyperproliferative diseases. In this connection, psoriasis,arthritis, inflammation, endometriosis, scarring, benign prostatichyperplasia, immunological diseases, autoimmune diseases andimmunodeficiency diseases are regarded as non-cancerous diseases, ofwhich arthritis, inflammation, immunological diseases, autoimmunediseases and immunodeficiency diseases are usually regarded asnon-hyperproliferative diseases. In this connection, brain cancer, lungcancer, squamous cell cancer, bladder cancer, gastric cancer, pancreaticcancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer,head cancer, neck cancer, oesophageal cancer, gynaecological cancer,thyroid cancer, lymphoma, chronic leukaemia and acute leukaemia are tobe regarded as cancerous diseases, all of which are usually regarded ashyperproliferative diseases. Especially cancerous cell growth andespecially cancerous cell growth mediated by Raf kinase is a diseasewhich is a target of the present invention. The pre-sent inventiontherefore relates to compounds according to the invention as medicamentsand/or medicament active ingredients in the treatment and/or prophylaxisof the said diseases and to the use of compounds according to theinvention for the preparation of a pharmaceutical for the treatmentand/or prophylaxis of the said diseases as well as to a method for thetreatment of the said diseases which comprises the administration of oneor more compounds according to the invention to a patient in need ofsuch an administration.

It can be shown that the compounds according to the invention have anantiproliferative action in vivo in a xenotransplant tumour model. Thecompounds according to the invention are administered to a patienthaving a hyperproliferative disease, for example to inhibit tumourgrowth, to reduce inflammation associated with a lymphoproliferativedisease, to inhibit trans-plant rejection or neurological damage due totissue repair, etc. The present compounds are suitable for prophylacticor therapeutic purposes. As used herein, the term “treatment” is used torefer to both prevention of diseases and treatment of pre-existingconditions. The prevention of proliferation is achieved byadministration of the compounds according to the invention prior to thedevelopment of overt disease, for example to prevent the growth oftumours, prevent metastatic growth, diminish restenosis associated withcardiovascular surgery, etc. Alternatively, the compounds are used forthe treatment of ongoing diseases by stabilising or improving theclinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a periodine of time whichis sufficient to allow the active agents to induce cell death or toinhibit migration, usually between about one hour and one week. In vitrotesting can be carried out using cultivated cells from a biopsy sample.The viable cells remaining after the treatment are then counted.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93)and models of transgenic animals (for example White et al., Oncogene,2001, 20, 7064-7072). For the determination of certain stages in thesignal transduction cascade, interacting compounds can be utilised inorder to modulate the signal (for example Stephens et al., BiochemicalJ., 2000, 351, 95-105). The compounds according to the invention canalso be used as reagents for testing kinase-dependent signaltransduction pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (for example Alessi et al., FEBS Lett. 1996,399, 3, pages333-338) or the basic myelin protein, are described in the literature(for example Campos-Gonzalez, R. and Glenney, Jr., J. R. 1992, J. Biol.Chem. 267, page 14535).

For the identification of kinase inhibitors, various assay systems areavailable. In scintillation proximity assay (Sorg et al., J. of.Biomolecular Screening, 2002, 7, 11-19) and flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate withγATP is measured. In the presence of an inhibitory compound, a decreasedradioactive signal, or none at all, is detectable. Furthermore,homogeneous time-resolved fluorescence resonance energy transfer(HTR-FRET) and fluorescence polarisation (FP) technologies are suitableas assay methods (Sills et al., J. of Biomolecular Screening, 2002,191-214).

Other non-radioactive ELISA assay methods use specificphospho-anti-bodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody (Ross et al., 2002, Biochem. J., just about to be published,manuscript BJ20020786).

There are many diseases associated with deregulation of cellularproliferation and cell death (apoptosis). The conditions of interestinclude, but are not limited to, the following. The compounds accordingto the invention are suitable for the treatment of various conditionswhere there is proliferation and/or migration of smooth muscle cellsand/or inflammatory cells into the intimal layer of a vessel, resultingin restricted blood flow through that vessel, for example in the case ofneointimal occlusive lesions. Occlusive graft vascular diseases ofinterest include atherosclerosis, coronary vascular disease aftergrafting, vein graft stenosis, peri-anastomatic prosthetic restenosis,restenosis after angioplasty or stent placement, and the like.

The compounds according to the invention are also suitable as p38 kinaseinhibitors.

Heteroarylureas which inhibit p38 kinase are described in WO 02/85859.

PRIOR ART

Pyridopyrimidines are described in WO 98/08846.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R^(1a), R^(1b), R^(1c),-   R^(1d), R^(1e),-   R^(2a), R^(2b) each, independently of one another, denote R, Hal,    CN, NO₂, NRR′, NHCOR, NHSO₂R, OR, CO—R, COOR, CO—NHR, OA, SA, SO₃R,    SO₂R and/or SO₂NHR,-   two adjacent radicals selected from R^(1a), R^(1b), R^(1c), R^(1d),    R^(1e) together also denote —O—CH₂—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—,-   R³ denotes Hal or OR,-   R, R′ each, independently of one another, denote H, A,    —[C(R⁴)₂]_(n)—Ar,    -   —[C(R⁴)₂]_(n)-Het, —[C(R⁴)₂]_(p)—O—C(R⁴)₂]_(q)—Ar,    -   —[C(R⁴)₂]_(p)—O—C(R⁴)₂]_(q)-Het,-   R⁴ denotes H or A,-   R⁵ denotes H or A,-   Ar denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di- or trisubstituted by Hal, A, OR⁴,    N(R⁴)₂, NO₂, CN, COOR⁴, CON(R⁴)₂, NR⁴COA, NR⁴SO₂A, COR⁴, SO₂N(R⁴)₂,    —[C(R⁴)₂]_(n)—COOR⁴, —O—[C(R⁴)₂]_(o)—COOR⁴, SO₃H and/or S(O)_(n)A,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen    (═O), ═S, ═N(R⁴)₂, Hal, A, —[C(R⁴)₂]_(n)—Ar,    —[C(R⁴)₂]_(n)-cycloalkyl, —[C(R⁴)₂]_(n)—OR⁴, —[C(R⁴)₂]_(n)—N(R⁴)₂,    NO₂, CN, —[C(R⁴)₂]_(n)—COOR⁴, —[C(R⁴)₂]_(n)—CON(R⁴)₂,    —[C(R⁴)₂]_(n)—NR⁴COA, NR⁴CON(R⁴)₂, —[C(R⁴)₂]_(n)—NR⁴SO₂A, COR⁴,    SO₂N(R⁴)₂ and/or S(O)_(n)A,-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    one or two CH₂ groups may be replaced by O or S atoms and/or by    —CH═CH— groups and/or in addition 1-7H atoms may be replaced by F,    -   or cyclic alkyl having 3-7 C atoms,-   Hal denotes F, Cl, Br or I,-   n denotes 0, 1, 2, 3 or 4,-   p denotes 1, 2, 3 or 4-   q denotes 0, 1, 2, 3 or 4,    and pharmaceutically usable derivatives, solvates, salts, tautomers    and stereoisomers thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.solvates are, for example, mono- or dihydrates or alkoxides.

The formula I also encompasses the tautomeric compounds of the formulaI.

If R³ denotes, for example, OH, the tautomeric compounds of the formulaIa are also encompassed

The term pharmaceutically usable derivatives is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds.

The term prodrug derivatives is taken to mean compounds of the formula Iwhich have been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to claims 1-10 and pharmaceutically usable derivatives,salts, solvates and stereoisomers thereof, characterised in that

a) a compound of the formula II

in which

R^(2a), R^(2b), R³ and R⁵ have the meanings indicated in claim 1,

is reacted with a compound of the formula III

in which R^(1a)—R^(1e) have the meanings indicated in claim 1,orb) a radical R³ is converted into another radical R³ by substituting ahalogen atom,and/ora base or acid of the formula I is converted into one of its salts.

Above and below, the radicals R^(1a), R^(1b), R^(1c), R^(1d), R^(1e),R^(2a), R^(2b), R³ and X have the meanings indicated for the formula I,unless expressly stated otherwise.

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethyl-propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoro-ethyl. A also denotes cycloalkyl.

Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl,cyclo-hexyl or cycloheptyl.

In a preferred embodiment, A also denotes unbranched or branched alkylhaving 1-10 C atoms, in which 1-7H atoms may be replaced by F.

R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) preferably each denote,independently of one another, H, A, OA or Hal.

R^(2a) and R^(2b) preferably denote H.

R³ preferably denotes Hal or OH.

R⁵ particularly preferably denotes alkyl having 1-6 C atoms, such as,for example, methyl, ethyl, propyl, or cyclic alkyl, such as, forexample, cyclo-propyl.

R, R′ preferably each denote, independently of one another, for example,H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, trifluoromethyl, phenyl, benzyl, pyridyl,pyrimidinyl, imidazolyl, piperidinyl, pyrrolidinyl, thienyl, indolyl orbenzyloxymethyl.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further-more preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso-indolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, furthermore preferably1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or-5-yl or 2,1,3-benzoxadiazol-5-yl. The heterocyclic radicals may also bepartially or fully hydrogenated. Het may thus also denote, for example,2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or-3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-di-hydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl,tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-,-4-, -5-, -6-, -7- or -8-iso-quinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylene-dioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)-phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butyl-phenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methyl-aminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxy-phenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethyl-amino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, furtherpreferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-,2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Hal preferably denotes F, Cl or Br, but also 1, particularly preferablyF or Cl. Throughout the invention, all radicals which occur more thanonce may be identical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to le, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R^(1a), R^(1b), R^(1c)    -   R^(1d), R^(1e), each, independently of one another, denote H, A,        OA and/or Hal;-   in Ib R^(2a)R^(2b) denote H;-   in Ic R³ denote Hal or OH;-   in Id A denotes unbranched or branched alkyl having 1-10 C atoms, in    which 1-7H atoms may be replaced by F, or cyclic alkyl having 3-7 C    atoms;-   in Ie R^(1a), R^(1b), R^(1c),    -   R^(1d), R^(1e) each, independently of one another, denote H, A,        OA and/or Hal,    -   R^(2a), R^(2b) denote H,    -   R³ denotes Hal or OH    -   R⁵ denotes H or A,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7H atoms may be replaced by F, or cyclic alkyl having        3-7 C atoms,    -   Hal denotes F, Cl, Br or I;        and pharmaceutically usable derivatives, salts, solvates,        tautomers and stereoisomers thereof, including mixtures thereof        in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methodn der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

If desired, the starting materials can also be formed in situ so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula I.

Compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula Ill.

The compounds of the formula II are novel, those of the formula III aregenerally known.

The reaction is generally carried out in an inert solvent, in thepresence of an organic base, such as triethylamine, dimethylaniline,pyridine or quinoline. Depending on the conditions used, the reactiontime is between a few minutes and 14 days, the reaction temperature isbetween about 0° and 150°, normally between 15° and 90°, particularlypreferably between 15 and 30° C.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methyl-glutamine. The aluminiumsalts of the compounds of the formula I are likewise included. In thecase of certain compounds of the formula I, acid-addition salts can beformed by treating these compounds with pharmaceutically acceptableorganic and inorganic acids, for example hydrogen halides, such ashydrogen chloride, hydrogen bromide or hydrogen iodide, other mineralacids and corresponding salts thereof, such as sulfate, nitrate orphosphate and the like, and alkyl- and monoarylsulfonates, such asethanesulfonate, toluenesulfonate and benzenesulfonate, and otherorganic acids and corresponding salts thereof, such as acetate,trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate,salicylate, ascorbate and the like. Accordingly, pharmaceuticallyacceptable acid-addition salts of the compounds of the formula I includethe following: acetate, adipate, alginate, arginate, aspartate,benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide,butyrate, camphorate, camphorsulfonate, caprylate, chloride,chlorobenzoate, citrate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate,gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate,heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate,lactate, lactobionate, malate, maleate, malonate, mandelate,metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylamino-ethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethyl-piperidine, glucamine, glucosamine,histidine, hydrabamine, isopropyl-amine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine. Thebase-addition salts of acidic compounds according to the invention areprepared by bringing the free acid form into contact with a sufficientamount of the desired base, causing the formation of the salt in aconventional manner. The free acid can be regenerated by bringing thesalt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone,a dissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts, solvates and physiologicallyfunctional derivatives thereof can also be administered in the form ofliposome delivery systems, such as, for example, small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from various phospholipids, such as, forexample, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal anti-bodies as individual carriers to which thecompound molecules are coupled. The compounds can also be coupled tosoluble polymers as targeted medicament carriers. Such polymers mayencompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol,polyhydroxy-ethylaspartamidophenol or polyethylene oxide polylysine,substituted by palmitoyl radicals. The compounds may furthermore becoupled to a class of biodegradable polymers which are suitable forachieving controlled release of a medicament, for example polylacticacid, poly-epsilon-caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions pre-pared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound of the formula I for thetreatment of neoplastic growth, for example colon or breast carcinoma,is generally in the range from 0.1 to 100 mg/kg of body weight of therecipient (mammal) per day and particularly typically in the range from1 to 10 mg/kg of body weight per day. Thus, the actual amount per dayfor an adult mammal weighing 70 kg is usually between 70 and 700 mg,where this amount can be administered as a single dose per day orusually in a series of part-doses (such as, for example, two, three,four, five or six) per day, so that the total daily dose is the same. Aneffective amount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound of the formula I per se. It can be assumed thatsimilar doses are suitable for the treatment of other conditionsmentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, especially for humans, in the treatment of tyrosinekinase-induced diseases. These diseases include the proliferation oftumour cells, pathological neovascularisation (or angiogenesis) whichpromotes the growth of solid tumours, ocular neovascularisation(diabetic retinopathy, age-induced macular degeneration and the like)and inflammation (psoriasis, rheumatoid arthritis and the like).

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts and solvates thereoffor the preparation of a medicament for the treatment or prevention ofcancer. Preferred carcinomas for the treatment originate from the groupcerebral carcinoma, urogenital tract carcinoma, carcinoma of thelymphatic system, stomach carcinoma, laryngeal carcinoma and lungcarcinoma. A further group of preferred forms of cancer are monocyticleukaemia, lung adeno-carcinoma, small-cell lung carcinomas, pancreaticcancer, glioblastomas and breast carcinoma.

Also encompassed is the use of the compounds according to claim 1according to the invention and/or physiologically acceptable salts andsolvates thereof for the preparation of a medicament for the treatmentor prevention of a disease in which angiogenesis is implicated.

Such a disease in which angiogenesis is implicated is an ocular disease,such as retinal vascularisation, diabetic retinopathy, age-inducedmacular degeneration and the like.

The use of compounds of the formula I and/or physiologically acceptable35 salts and solvates thereof for the preparation of a medicament forthe treatment or prevention of inflammatory diseases also falls withinthe scope of the present invention. Examples of such inflammatorydiseases include rheumatoid arthritis, psoriasis, contact dermatitis,delayed hyper-sensitivity reaction and the like.

Also encompassed is the use of the compounds of the formula I and/orphysiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of atyrosine kinase-induced disease or a tyrosine kinase-induced conditionin a mammal, in which to this method a therapeutically effective amountof a compound of the formula I is administered to a sick mammal in needof such treatment. The therapeutic amount varies according to thespecific disease and can be determined by the person skilled in the artwithout undue effort.

The present invention also encompasses the use of the compounds of theformula I and/or physiologically acceptable salts and solvates thereoffor the preparation of a medicament for the treatment or prevention ofretinal vascularisation.

Methods for the treatment or prevention of ocular diseases, such asdiabetic retinopathy and age-induced macular degeneration, are likewisepart of the invention. The use for the treatment or prevention ofinflammatory diseases, such as rheumatoid arthritis, psoriasis, contactdermatitis and delayed hypersensitivity reaction, as well as thetreatment or prevention of bone pathologies from the group osteosarcoma,osteoarthritis and rickets, likewise falls within the scope of thepresent invention.

The expression “tyrosine kinase-induced diseases or conditions” refersto pathological conditions that depend on the activity of one or moretyrosine kinases. Tyrosine kinases either directly or indirectlyparticipate in the signal transduction pathways of a variety of cellularactivities, including proliferation, adhesion and migration anddifferentiation. Diseases associated with tyrosine kinase activityinclude proliferation of tumour cells, pathological neovascularisationthat promotes the growth of solid tumours, ocular neovascularisation(diabetic retinopathy, age-induced macular degeneration and the like)and inflammation (psoriasis, rheumatoid arthritis and the like).

The compounds of the formula I can be administered to patients for thetreatment of cancer. The present compounds inhibit tumour angiogenesis,thereby affecting the growth of tumours (J. Rak et al. Cancer Research,55:4575-4580, 1995). The angiogenesis-inhibiting properties of thepresent compounds of the formula I are also suitable for the treatmentof certain forms of blindness related to retinal neovascularisation.

The compounds of the formula I are also suitable for the treatment ofcertain bone pathologies, such as osteosarcoma, osteoarthritis andrickets, also known as oncogenic osteomalacia (Hasegawa et al., SkeletalRadiol. 28, pp. 41-45,1999; Gerber et al., Nature Medicine, Vol. 5, No.6, pp. 623-628, June 1999). Since VEGF directly promotes osteoclasticbone resorption through KDR/Flk-1 expressed in mature osteoclasts (FEBSLet. 473:161-164 (2000); Endocrinology, 141:1667 (2000)), the presentcompounds are also suitable for the treatment and prevention ofconditions related to bone resorption, such as osteoporosis and Paget'sdisease. The compounds can also be used for the reduction or preventionof tissue damage which occurs after cerebral ischaemic events, such asstrokes, by reducing cerebral oedema, tissue damage and reperfusioninjury following ischaemia (Drug News Perspect 11:265-270 (1998); J.Clin. Invest 104:1613-1620 (1999)).

The invention thus relates to the use of compounds of the formula I, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, for the preparation of amedicament for the treatment of diseases in which the inhibition,regulation and/or modulation of kinase signal transduction plays a role.

Preference is given here to kinases selected from the group of thetyrosine kinases and Raf kinases.

The tyrosine kinases are preferably TIE-2, VEGFR, PDGFR, FGFR and/orFLT/KDR.

Preference is given to the use of compounds of the formula I, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios,

for the preparation of a medicament for the treatment of diseases whichare influenced by inhibition of tyrosine kinases by the compoundsaccording to claim 1.

Particular preference is given to the use for the preparation of amedicament for the treatment of diseases which are influenced byinhibition of TIE-2, VEGFR, PDGFR, FGFR and/or FLT/KDR by the compoundsaccording to claim 1.

Especial preference is given to the use for the treatment of a diseasewhere the disease is a solid tumour.

The solid tumour is preferably selected from the group of tumours of thesquamous epithelium, the bladder, the stomach, the kidneys, of head andneck, the oesophagus, the cervix, the thyroid, the intestine, the liver,the brain, the prostate, the urogenital tract, the lymphatic system, thestomach, the larynx and/or the lung.

The solid tumour is furthermore preferably selected from the group lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of a tumourof the blood and immune system, preferably for the treatment of a tumourselected from the group of acute myelotic leukaemia, chronic myeloticleukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

The invention furthermore relates to the use of the compounds of theformula I for the treatment of a disease in which angiogenesis isimplicated.

The disease is preferably an ocular disease.

The invention furthermore relates to the use for the treatment ofretinal vascularisation, diabetic retinopathy, age-induced maculardegeneration and/or inflammatory diseases.

The inflammatory disease is preferably selected from the grouprheumatoid arthritis, psoriasis, contact dermatitis and delayedhypersensitivity reaction.

The invention furthermore relates to the use of the compounds of theformula I for the treatment of bone pathologies, where the bonepathology originates from the group osteosarcoma, osteoarthritis andrickets.

The compounds of the formula I are suitable for the preparation of amedicament for the treatment of diseases which are caused, mediatedand/or propagated by Raf kinases, where the Raf kinase is selected fromthe group consisting of A-Raf, B-Raf and Raf-1.

Preference is given to the use for the treatment of diseases, preferablyfrom the group of the hyperproliferative and non-hyperproliferativediseases.

These are cancer diseases or non-cancerous diseases.

The non-cancerous diseases are selected from the group consisting ofpsoriasis, arthritis, inflammation, endometriosis, scarring, benignprostatic hyperplasia, immunological diseases, autoimmune diseases andimmuno-deficiency diseases.

The cancerous diseases are selected from the group consisting of braincancer, lung cancer, squamous cell cancer, bladder cancer, gastriccancer, pancreatic cancer, hepatic cancer, renal cancer, colorectalcancer, breast cancer, head cancer, neck cancer, oesophageal cancer,gynaecological cancer, thyroid cancer, lymphoma, chronic leukaemia andacute leukaemia.

The compounds of the formula I may also be administered at the same timeas other well-known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, in the case of bone conditions, combinations that would befavourable include those with antiresorptive bisphosphonates, such asalendronate and risedronate, integrin blockers (as defined furtherbelow), such as αvβ3 antagonists, conjugated oestrogens used in hormonereplacement therapy, such as Prempro®, Premarin® and Endometrion®;selective oestrogen receptor modulators (SERMs), such as raloxifene,droloxifene, CP-336,156 (Pfizer) and lasofoxifene, cathepsin Kinhibitors, and ATP proton pump inhibitors.

The present compounds are also suitable for combination with knownanti-cancer agents. These known anti-cancer agents include thefollowing: oestrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxic agents, antiproliferativeagents, prenyl-protein transferase inhibitors, HMG-CoA reductaseinhibitors, HIV protease inhibitors, reverse transcriptase inhibitorsand further angiogenesis inhibitors. The present compounds areparticularly suitable for administration at the same time asradiotherapy. The synergistic effects of inhibiting VEGF in combinationwith radiotherapy have been described in the art (see WO 00/61186).

“Oestrogen receptor modulators” refers to compounds which interfere withor inhibit the binding of oestrogen to the receptor, regardless ofmechanism. Examples of oestrogen receptor modulators include, but arenot limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY 117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl2,2-dimethyl-propanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646.

“Androgen receptor modulators” refers to compounds which interfere withor inhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere withor inhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,a-difluoromethylornithine, ILX23-7553,trans-N-(4′-hydroxyphenyl)retinamide and N-4-carboxyphenyl-retinamide.

“Cytotoxic agents” refers to compounds which result in cell deathprimarily through direct action on the cellular function or inhibit orinterfere with cell myosis, including alkylating agents, tumour necrosisfactors, intercalators, microtubulin inhibitors and topoisomeraseinhibitors.

Examples of cytotoxic agents include, but are not limited to,tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine,carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosylate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methylpyridine)Platinum, benzylguanine,glufosfamide, GPX100,(trans,trans,trans)bis-mu-(hexane-1,6-diamine)-mu-[diamine-Platinum(II)]bis[diamine(chloro)Platinum(II)]tetrachloride,diarisidinyl-spermine, arsenictrioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine,zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone,pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston,3′-de-amino-3′-morpholino-13-deoxo-10-hydroxycaminomycin, annamycin,gala-rubicin, elinafide, MEN10755 and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyldaunorubicin (see WO00/50032).

Examples of microtubulin inhibitors include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exobenzylidenechartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propan-amine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H)-dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin,BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide,sobuzoxane, 2′-dimethylamino-2′-deoxyetoposide, GL331,N-[2-(dimethyl-amino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carbox-amide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexo-hydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,6,9-bis[(2-amino-ethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]-acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-oneand dimesna.

“Antiproliferative agents” include antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 andanti-metabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,neizarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-di-hydrobenzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-mannohepto-pyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b]-1,4-thiazin-6-yl-(S)-ethyl]-2,5-thie-noyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,1′-diazatetracyclo-(7.4.1.0.0)tetradeca-2,4,6-trien-9-ylaceticacid ester, swainsonine, lome-trexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N⁴-palmitoyl-1-B-D-arabinofuranosyl cytosine and3-aminopyridine-2-carboxaldehyde thio-semicarbazone. “Antiproliferativeagents” also include monoclonal anti-bodies to growth factors other thanthose listed under “angiogenesis in-hibitors”, such as trastuzumab, andtumour suppressor genes, such as p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example).

The invention furthermore relates to the use of the compounds of theformula I for the preparation of a medicament for the treatment ofdiseases, where the disease is characterised by disturbed angiogenesis.The disease is preferably cancer diseases.

The disturbed angiogenesis preferably results from disturbed VEGFR-1,VEGFR-2 and/or VEGFR-3 activity.

Particular preference is therefore also given to the use of thecompounds according to the invention for the preparation of a medicamentfor the inhibition of VEGFR-2 activity.

Assays

The compounds of the formula I described in the examples were tested bythe assays described below and were found to have kinase inhibitoryactivity. Other assays are known from the literature and could readilybe performed by the person skilled in the art (see, for example,Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem.274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk etal., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst52:413-427; Nicosia et al., In Vitro 18:538-549).

VEGF Receptor Kinase Assay

VEGF receptor kinase activity is measured by incorporation ofradio-labelled phosphate into 4:1 polyglutamic acid/tyrosine substrate(pEY). The phosphorylated pEY product is trapped on a filter membraneand the incorporation of radiolabelled phosphate is quantified byscintillation counting.

Materials VEGF Receptor Kinase

The intracellular tyrosine kinase domains of human KDR (Terman, B. I. etal. Oncogene (1991) Vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya, M. etal. Oncogene (1990) Vol. 5, pp. 519-524) were cloned as glutathioneS-transferase (GST) gene fusion proteins. This was accomplished bycloning the cytoplasmic domain of the KDR kinase as an in frame fusionat the carboxyl terminus of the GST gene. Soluble recombinant GST-kinasedomain fusion proteins were expressed in Spodoptera frugiperda (Sf21)insect cells (Invitrogen) using a baculovirus expression vector (pAcG2T,Pharmingen).

Lysis Buffer

50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.5% of TritonX-100, 10% of glycerol, 10 mg/ml each of leupeptin, pepstatin andaprotinin and 1 mM phenylmethylsulfonyl fluoride (all Sigma).

Wash Buffer

50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% of TritonX-100, 10% of glycerol, 10 mg/ml each of leupeptin, pepstatin andaprotinin and 1 mM phenylmethylsulfonyl fluoride.

Dialysis Buffer

50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% of TritonX-100, 50% of glycerol, 10 mg/ml each of leupeptin, pepstatin andaprotinin and 1 mM phenylmethylsulfonyl fluoride.

10×reaction buffer200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl₂, 10 mM DTT and 5 mg/ml ofbovine serum albumin [BSA] (Sigma).

Enzyme Dilution Buffer

50 mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT, 10% of glycerol, 100 mg/ml ofBSA.

10× substrate

750 pg/ml of poly(glutamic acid/tyrosine; 4:1) (Sigma).

Stop Solution

30% of trichloroacetic acid, 0.2 M sodium pyrophosphate (both Fisher).

Wash Solution

15% of trichloroacetic acid, 0.2 M sodium pyrophosphate.

Filter Plates

Millipore #MAFC NOB, GF/C glass-fibre 96-well plate.

Method A—Protein Purification 1. Sf21 cells were infected withrecombinant virus at a multiplicity of infection of 5 virusparticles/cell and grown at 27° C. for 48 hours.

2. All steps were performed at 4° C. Infected cells were harvested bycentrifugation at 1000×g and lysed at 4° C. for 30 minutes with 1/10volume of lysis buffer followed by centrifugation at 100000×g for 1hour. The supernatant was then passed over a glutathione Sepharose acid(Pharmacia) equilibrated with lysis buffer and washed with 5 volumes ofthe same buffer followed by 5 volumes of wash buffer. RecombinantGST-KDR protein was eluted with wash buffer/10 mM reduced glutathione(Sigma) and dialysed against dialysis buffer.

Method B—VEGF Receptor Kinase Assay 1. Add 5 μl of inhibitor or controlto the assay in 50% DMSO. 2. Add 35 μl of reaction mixture containing 5μl of 10× reaction buffer, 5 μl of 25 mM ATP/10 μCi[³³P]ATP (Amersham)and 5 μl of 10× substrate. 3. Start the reaction by the addition of 10μl of KDR (25 nM) in enzyme dilution buffer. 4. Mix and incubate at roomtemperature for 15 minutes. 5. Stop the reaction by the addition of 50μl of stop solution. 6. Incubate at 4° C. for 15 minutes. 7. Transfer a90 μl aliquot to filter plate. 8. Aspirate and wash 3 times with washsolution. 9. Add 30 μl of scintillation cocktail, seal plate and countin a Wallace Microbeta scintillation counter. Human Umbilical VeinEndothelial Cell Mitogenesis Assay

Expression of VEGF receptors that mediate mitogenic responses to thegrowth factor is largely restricted to vascular endothelial cells. Humanumbilical vein endothelial cells (HUVECs) in culture proliferate inresponse to VEGF treatment and can be used as an assay system toquantify the effects of KDR kinase inhibitors on VEGF stimulation. Inthe assay described, quiescent HUVEC monolayers are treated with vehicleor test compound 2 hours prior to addition of VEGF or basic fibroblastgrowth factor (bFGF). The mitogenic response to VEGF or bFGF isdetermined by measuring the incorporation of [³H]thymidine into cellularDNA.

Materials HUVECs

HUVECs frozen as primary culture isolates are obtained from CloneticsCorp. Cells are obtained in endothelial growth medium (EGM; Clonetics)and are used for mitogenic assays at passages 3-7.

Culture Plates

NUNCLON 96-well polystyrene tissue culture plates (NUNC #167008).

Assay Medium

Dulbecco's modification of Eagle's medium containing 1g/ml of glucose(low-glucose DMEM; Mediatech) plus 10% (v/v) foetal bovine serum(Clonetics).

Test Compounds

Working stock solutions of test compounds are diluted serially in 100%dimethyl sulfoxide (DMSO) to 400 times greater than their desired finalconcentrations. Final dilutions to 1× concentration are made in assaymedium immediately prior to addition to cells.

10×Growth Factors

Solutions of human VEGF 165 (500 ng/ml; R&D Systems) and bFGF (10 ng/ml;R&D Systems) are prepared in assay medium.

10×[³H]thymidine

[Methyl-3H]thymidine (20 Ci/mmol; Dupont-NEN) is diluted to 80 μCi/ml inlow-glucose DMEM medium.

Cell Wash Medium

Hank's balanced salt solution (Mediatech) containing 1 mg/ml of bovineserum albumin (Boehringer-Mannheim).

Cell Lysis Solution 1 N NaOH, 2% (w/v) Na₂CO₃. Method 1

HUVEC monolayers maintained in EGM are harvested by trypsinization andplated out at a density of 4000 cells per 100 μl of assay medium perwell in 96-well plates. Cell growth is arrested for 24 hours at 37° C.in a humidified atmosphere containing 5% CO₂.

Method 2

Growth-arrest medium is replaced by 100 μl of assay medium containingeither vehicle (0.25% [v/v] DMSO) or the desired final concentration oftest compound. All determinations are performed in triplicate. Cells arethen incubated at 37° C./5% CO₂ for 2 hours to allow test compounds toenter cells.

Method 3

After the 2-hour pre-treatment periodine, cells are stimulated byaddition of 10 μl/well of either assay medium, 10×VEGF solution or10×bFGF solution. Cells are then incubated at 37° C./5% CO₂.

Method 4

After 24 hours in the presence of growth factors, 10×[³H]thymidine (10μl/well) is added.

Method 5

Three days after addition of [³H]thymidine, medium is removed byaspiration, and cells are washed twice with cell wash medium (400μl/well followed by 200 μl/well). The washed, adherent cells are thensolubilised by addition of cell lysis solution (100 μl/well) and warmingat 37° C. for 30 minutes. Cell lysates are transferred to 7 ml glassscintillation vials containing 150 μl of water. Scintillation cocktail(5 ml/vial) is added, and cell-associated radioactivity is determined byliquid scintillation spectroscopy. According to these assays, thecompounds of the formula I are inhibitors of VEGF and are thus suitablefor the inhibition of angiogenesis, such as in the treatment of oculardiseases, for example diabetic retinopathy, and for the treatment ofcarcinomas, for example solid tumours. The present compounds inhibitVEGF-stimulated mitogenesis of human vascular endothelial cells inculture with IC₅₀ values of 0.01-5.0 μM. These compounds also showselectivity over related tyrosine kinases (for example FGFR1 and the Srcfamily; for relationship between Src kinases and VEGFR kinases, seeEliceiri et al., Molecular Cell, Vol. 4, pp. 915-924, December 1999).

The TIE-2 tests can be carried out, for example, analogously to themethods indicated in WO 02/44156.

The assay determines the inhibiting activity of the substances to betested in the phosphorylation of the substrate poly(Glu, Tyr) by Tie-2kinase in the presence of radioactive ³³P-ATP. The phosphorylatedsubstrate binds to the surface of a “flashplate” microtitre plate duringthe incubation time.

After removal of the reaction mixture, the microtitre plate is washed anumber of times and the radioactivity on its surface is subsequentlymeasured. An inhibiting effect of the substances to be measured resultsin lower radioactivity compared with an undisturbed enzymatic reaction.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to a value of between 2 and 10, dependingon 10 the constitution of the end product, the mixture is extracted withethyl acetate or dichloromethane, the phases are separated, the organicphase is dried over sodium sulfate and evaporated, and the product ispurified by chromatography on silica gel and/or by crystallisation. Rfvalues on silica gel; eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺

APCI-MS (atmospheric pressure chemical jonisation−mass spectrometry)(M+H)⁺.

Determination of the retention time R_(f) by means of HPLC:

Column: Chromolith SpeedRPD, 50×4.6 mm² (Merck)

Gradient: 5.0 min, t=0 min, A:B=95:5, t=4.4 min: A:B=25:75,

-   -   t=4.5 min to t=5.0 min: A:B=0:100

Flow rate: 3.00 ml/min

-   -   Eluent A: water+0.1% of TFA (trifluoroacetic acid)    -   Eluent B: acetonitrile+0.08% of TFA

Wavelength: 220 nm

EXAMPLE 1 Preparation of1-[4-(4-chloro-2-methyl-3H-imidazo[4,5-c]pyridin-3-yl-methyl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea(“A1”)

1.1 A solution of 10.0 g of 3,4-diamino-2-chloropyridine and 6.62 ml ofacetic anhydride in 100 ml of THF is stirred at room temperature for 16hours. The product is separated off and dried, giving 7.3 g ofN-(4-amino-2-chloropyridin-3-yl)acetamide (“1”).

1.2 7.3 g of “1” is dissolved in DMF and cooled to 5°. A solution of5.05 g of potassium tert-butoxide in DMF is added dropwise, and stirringis continued with ice-cooling for 45 minutes. A solution of 9.38 g of4-nitrobenzyl bromide in DMF is then added dropwise. The mixture isstirred at room temperature under a nitrogen atmosphere for a further 16hours. The solvent is removed, and the residue is taken up in water. Theprecipitated product is separated off and dried, giving 3.5 g ofN-(4-amino-2-chloro-pyridin-3-yl)-N-(4-nitrobenzyl)acetamide (“2”).

1.3 A solution of 3.5 g of “2” and 13 ml of 1 N NaOH in dioxane isrefluxed for 16 hours. The mixture is subjected to conventional work-up,giving 3.0 g of4-chloro-2-methyl-3-(4-nitrobenzyl)-3H-imidazo[4,5-c]pyridine (“3”)

1.4 3.0 g of “3” in 60 ml of THF is hydrogenated under standardconditions in the presence of 0.6 g of Raney nickel. The catalyst issubsequently separated off and subjected to conventional work-up, giving3.2 g of 4-chloro-2-methyl-3-(4-aminobenzyl)-3H-imidazo[4,5-c]pyridine(“4”), which is converted into the hydrochloride (“4a”).

1.5 A solution of 92.76 mg of “4a”, 43.4 μl of2-fluoro-5-trifluoromethyl-phenyl isocyanate and 51.0 μl ofN-ethyldiisopropylamine in 3 ml of DMF is stirred at room temperaturefor 16 hours. The residue is purified by chromatography, giving 30.7 mgof “A1”, R_(f) 3.97.

The following compounds are obtained analogously

-   1-[4-(4-chloro-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(3-trifluoromethylphenyl)urea,    R_(f) 3.84;-   1-[4-(4-chloro-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(3-fluoro-5-trifluoromethylphenyl)urea,    R_(f) 4.05;-   1-[4-(4-chloro-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(4-chloro-5-trifluoromethylphenyl)urea,    R_(f) 3.97;-   1-[4-(4-chloro-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea,    R_(f) 4.32;-   1-[4-(4-chloro-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(3-trifluoromethylphenyl)urea,    R_(f) 4.19;-   1-[4-(4-chloro-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(3-fluoro-5-trifluoromethylphenyl)urea,    R_(f) 4.37;-   1-[4-(4-chloro-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(4-chloro-5-trifluoromethylphenyl)urea,    R_(f) 4.45;-   1-[4-(4-chloro-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea,    R_(f) 4.05;-   1-[4-(4-chloro-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea,    R_(f) 4.35.

EXAMPLE 2

A solution of 50 mg of “A1” in 1 ml of formic acid (98-100%) is refluxedfor 8 hours and subsequently purified via an RP18 column, giving 3 mg of1-[4-(4-hydroxy-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea(“A2”), R_(f) 3.28.

The following compounds are obtained analogously

-   1-[4-(4-hydroxy-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(3-trifluoromethylphenyl)urea,    R_(f) 3.36;-   1-[4-(4-hydroxy-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(3-fluoro-5-trifluoromethylphenyl)urea,    R_(f) 3.36;-   1-[4-(4-hydroxy-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(4-chloro-5-trifluoromethylphenyl)urea,    R_(f) 3.41;-   1-[4-(4-hydroxy-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea,    R_(f) 3.55;-   1-[4-(4-hydroxy-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(3-trifluoromethylphenyl)urea,    R_(f) 3.47;-   1-[4-(4-hydroxy-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(3-fluoro-5-trifluoromethylphenyl)urea,    R_(f) 3.63;-   1-[4-(4-hydroxy-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(4-chloro-5-trifluoromethylphenyl)urea,    R_(f) 3.71;-   1-[4-(4-hydroxy-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea,    R_(f) 3.44;-   1-[4-(4-hydroxy-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea,    R_(f) 3.6.

The following examples relate to medicaments:

EXAMPLE A Injection Vials

A solution of 100g of an active ingredient of the formula I and 5g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1g of an active ingredient of the formula I,9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 11 and sterilised by irradiation.This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula 1, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. A compound or compounds of formula I

in which R^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(2a), R^(2b) each,independently of one another, is R, Hal, CN, NO₂, NRR′, NHCOR, NHSO₂R,OR, CO—R, COOR, CO—NHR, OA, SA, SO₃R, SO₂R or SO₂NHR, or two adjacentradicals selected from R^(1a), R^(1b), R^(1c), R^(1d), R^(1e) togetherare —O—CH₂—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—, R³ is Hal or OR, R, R′each, independently of one another, is H, A, —[C(R⁴)₂]_(n)—Ar,—[C(R⁴)₂]_(n)-Het, —[C(R⁴)₂]_(p)—O—C(R⁴)₂]_(q)—Ar, or—[C(R⁴)₂]_(p)—O—C(R⁴)₂]_(q)-Het, R⁴ is H or A, R⁵ is H or A, Ar isphenyl, naphthyl or biphenyl, each of which is un-substituted or mono-,di- or trisubstituted by Hal, A, OR⁴, N(R⁴)₂, NO₂, CN, COOR⁴, CON(R⁴)₂,NR⁴COA, NR⁴SO₂A, COR⁴, SO₂N(R⁴)₂, —[C(R⁴)₂]_(n)—COOR⁴,—O—[C(R⁴)₂]_(o)—COOR⁴, SO₃H or S(O)_(n)A, Het is a mono- or bicyclicsaturated, unsaturated or aromatic heterocycle having 1 to 4 N, O or Satoms, which optionally are unsubstituted or mono-, di- ortrisubstituted by carbonyl oxygen (═O), ═S, ═N(R⁴)₂, Hal, A,—[C(R⁴)₂]_(n)—Ar, —[C(R⁴)₂]_(n)-cycloalkyl, —[C(R⁴)₂]_(n)—OR⁴,—[C(R⁴)₂]_(n)—N(R⁴)₂, NO₂, CN, —[C(R⁴)₂]_(n)—COOR⁴,—[C(R⁴)₂]_(n)—CON(R⁴)₂, —[C(R⁴)₂]_(n)—NR⁴COA, NR⁴CON(R⁴)₂,—[C(R⁴)₂]_(n)—NR⁴SO₂A, COR⁴, SO₂N(R⁴)₂ or S(O)_(n)A, A denotes isunbranched or branched alkyl having 1-10 C atoms, in which one or twoCH₂ groups optionally are replaced by O or S atoms or by —CH═CH— groups,and in which 1-7H atoms optionally are replaced by F, or cyclic alkylhaving 3-7 C atoms, Hal is F, Cl, Br or I, n is 0, 1, 2, 3 or 4, p is 1,2, 3 or 4 q is 0, 1, 2, 3 or 4-, or physiologically acceptablederivatives, solvates, salts, tautomers or stereoisomers of saidcompound or compounds of formula I or mixtures thereof in all ratios. 2.The compound or compounds according to claim 1 in which R^(1a), R^(1b),R^(1c), R^(1d), R^(1e) each, independently of one another, is H, A, OAor Hal.
 3. The compound or compounds according to claim 1 in whichR^(2a), R^(2b) is H.
 4. The compound or compounds according to claim 1in which R³ is Hal or OH.
 5. The compound or compounds according toclaim 1 in which A is unbranched or branched alkyl having 1-10 C atoms,in which 1-7H atoms optionally are replaced by F, or cyclic alkyl having3-7 C atoms.
 6. The compound or compounds according to claim 1 in whichR^(1a), R^(1b), R^(1c), R^(1d), R^(1e) each, independently of oneanother, is H, A, OA or Hal, R^(2a), R^(2b) is H, R³ is Hal or OH, R⁵ isH or A, A is unbranched or branched alkyl having 1-10 C atoms, in which1-7H atoms optionally is replaced by F, or cyclic alkyl having 3-7 Catoms, and Hal is F, Cl, Br or I.
 7. The compound or compounds accordingto claim 1, selected from the group consisting of:1-[4-(4-chloro-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea,1-[4-(4-chloro-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(3-trifluoromethylphenyl)urea,1-[4-(4-chloro-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(3-fluoro-5-trifluoromethylphenyl)urea,1-[4-(4-chloro-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(4-chloro-5-trifluoromethylphenyl)urea,1-[4-(4-chloro-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea,1-[4-(4-chloro-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(3-trifluoromethylphenyl)urea,1-[4-(4-chloro-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(3-fluoro-5-trifluoromethylphenyl)urea,1-[4-(4-chloro-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(4-chloro-5-trifluoromethylphenyl)urea,1-[4-(4-chloro-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea,1-[4-(4-chloro-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea,1-[4-(4-hydroxy-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea,1-[4-(4-hydroxy-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(3-trifluoromethylphenyl)urea,1-[4-(4-hydroxy-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(3-fluoro-5-trifluoromethylphenyl)urea,1-[4-(4-hydroxy-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(4-chloro-5-trifluoromethylphenyl)urea,1-[4-(4-hydroxy-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea,1-[4-(4-hydroxy-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(3-trifluoromethylphenyl)urea,1-[4-(4-hydroxy-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(3-fluoro-5-trifluoromethylphenyl)urea,1-[4-(4-hydroxy-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(4-chloro-5-trifluoromethylphenyl)urea,1-[4-(4-hydroxy-2-methyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea,1-[4-(4-hydroxy-2-cyclopropyl-3H-imidazo[4,5-c]pyridin-3-ylmethyl)-phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea,physiologically acceptable derivatives, solvates, salts, tautomers andstereoisomers thereof, and mixtures thereof in all ratios.
 8. A processfor the preparation of a compound or compounds of the formula Iaccording to claim 1, characterised in that a) a compound of the formulaII

in which R^(2a), R^(2b), R³ and R⁵ have the meanings indicated in claim1, is reacted with a compound of the formula III

in which R^(1a)—R^(1e) have the meanings indicated in claim 1, or b) aradical R³ is converted into another radical R³ by substituting ahalogen atom, or a base or acid of the formula I is converted into oneof its salts.
 9. A medicament or medicaments comprising at least onecompound of the formula I according to claim 1 in a pharmaceuticalformulation and further optionally comprising excipients or adjuvants.10. A method comprising administering the medicament or medicaments ofclaim 1 to a subject having one or more diseases in which inhibition,regulation or modulation of kinase signal transduction plays a role. 11.The method of claim 10, wherein the kinases are selected from the groupconsisting of the tyrosine kinases and Raf kinases.
 12. The method ofclaim 11, wherein the tyrosine kinases are TIE-2, VEGFR, PDGFR, FGFR orFLT/KDR.
 13. The method of claim 11 wherein one or more of said diseasesare influenced by inhibition of tyrosine kinases by said one or moremedicaments.
 14. The method of claim 13 wherein one or more of saiddiseases are influenced by inhibition of TIE-2, VEGFR, PDGFR, FGFR orFLT/KDR by said one or more medicaments.
 15. The method of claim 13,wherein one or more of said diseases is a solid tumour.
 16. The methodof claim 15, wherein the solid tumour originates from squamousepithelium, bladder, stomach, kidneys, head, neck, esophagus, cervix,thyroid, intestine, liver, brain, prostate, urogenital tract, lymphaticsystem, stomach, larynx or lung cancer.
 17. The method of claim 15,wherein the solid tumour originates from monocytic leukaemia, lungadenocarcinoma, small-cell lung carcinoma, pancreatic cancer,glioblastoma or breast carcinoma.
 18. The method of claim 15, whereinthe solid tumour originates from lung adenocarcinoma, small-cell lungcarcinomas, pancreatic cancer, glioblastoma, colon carcinoma or breastcarcinoma.
 19. The method of claim 13, wherein one or more of saiddiseases is a tumour of the blood or immune system.
 20. The method ofclaim 19, wherein the tumour originates from acute myelotic leukaemia,chronic myelotic leukaemia, acute lymphatic leukaemia or chroniclymphatic leukaemia.
 21. The method of claim 13 wherein one or more ofsaid diseases is a disease in which angiogenesis is implicated.
 22. Themethod of claim 21, wherein one or more of said diseases is an oculardisease.
 23. The method of claim 13 wherein one or more of said diseasesis retinal vascularisation, diabetic retinopathy, age-induced maculardegeneration or an inflammatory disease.
 24. The method of claim 23,wherein the inflammatory disease originates from rheumatoid arthritis,psoriasis, contact dermatitis or delayed hypersensitivity reaction. 25.The method of claim 13 wherein one or more of said diseases isosteosarcoma, osteoarthritis or rickets.
 26. A method comprising,administering the compound or compounds of claim 1 to a subject havingone or more solid tumours, wherein a therapeutically effective amount ofa said compound or compounds is administered in combination with acompound selected from the group consisting of an oestrogen receptormodulator, an androgen receptor modulator, a retinoid receptormodulator, a cytotoxic agent, an antiproliferative agent, aprenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, anHIV protease inhibitor, a reverse transcriptase inhibitor and and anangiogenesis inhibitor.
 27. A method comprising, administering thecompound or compounds of claim 1 to a solid tumor or tumours, wherein atherapeutically effective amount of a said compound or compounds isadministered in combination with radiotherapy and a second compoundselected from the group consisting of an oestrogen receptor modulator,an androgen receptor modulator, a retinoid receptor modulator, acytotoxic agent, an antiproliferative agent, a prenyl-proteintransferase inhibitor, an HMG-CoA reductase inhibitor, an HIV proteaseinhibitor, a reverse transcriptase inhibitor and an angiogenesisinhibitor.
 28. The method of claim 13 wherein one or more of saiddiseases are based on disturbed TIE-2 activity, wherein atherapeutically effective amount of said medicament or medicaments isadministered in combination with a growth factor receptor inhibitor. 29.The method of claim 10 wherein one or more of said diseases are caused,mediated or propagated by Raf kinases.
 30. The method of claim 29,wherein the Raf kinase is selected from the group consisting of A-Raf,B-Raf and Raf-1.
 31. The method of claim 29, wherein one or more of saiddiseases are selected from the group consisting of hyperproliferativeand non-hyperproliferative diseases.
 32. The method of claim 29, whereinone or more of said diseases is cancer.
 33. The method of claim 29,wherein one or more of said diseases is noncancerous.
 34. The method ofclaim 33, wherein said one or more non-cancerous diseases are selectedfrom the group consisting of psoriasis, arthritis, inflammation,endometriosis, scarring, benign prostatic hyperplasia, immunologicaldiseases, autoimmune diseases and immunodeficiency diseases.
 35. Themethod of claim 32, wherein one or more of said diseases are selectedfrom the group consisting of brain cancer, lung cancer, squamous cellcancer, bladder cancer, gastric cancer, pancreatic cancer, hepaticcancer, renal cancer, colorectal cancer, breast cancer, head cancer,neck cancer, oesophageal cancer, gynaecological cancer, thyroid cancer,lymphoma, chronic leukaemia and acute leukaemia.